Genetic variation in Down syndrome associated congenital heart defects Open Access
Locke, Adam Edward (2010)
Abstract
Trisomy 21, the chromosomal abnormality responsible for Down
syndrome (DS), is a complex
condition with many characteristic symptoms as well as an increased
risk for numerous
congenital anomalies. The combination of these anomalies is often
severe, with as few as 20% of
conceptuses with trisomy 21 surviving to term. Heart defects are
among the most common
congenital anomalies associated with Down syndrome (DS), affecting
nearly half of all people
with DS. Of those with a congenital heart defect, nearly 20% have
an atrioventricular septal
defect (AVSD), representing a nearly 2000-fold increased risk of
AVSD compared to the general
population.
Through a multi-site recruitment effort, we have ascertained
individuals with DS who have a
complete balanced AVSD (cases) and those who have structurally
normal hearts (controls) and
their parents. Using this carefully selected sample, we test
several different hypotheses aimed
toward identifying the genetic variation underlying susceptibility
to AVSD in people with DS.
First, we test the common disease/common variant hypothesis by
testing common single
nucleotide (SNP) variation initially in specific candidate genes,
and subsequently throughout the
genome for association with AVSD. We further extend the common
disease/common variant
hypothesis genome-wide by identifying and test deletions for
association with AVSD.
Finally, we also explore the common disease/rare variant hypothesis
in two ways. We first test for
accumulation of rare copy number variants (CNVs) in cases with AVSD
compared to controls.
Additionally, we attempt to identify rare SNPs or
insertions/deletions of functional consequence
through the resequencing of candidate genes. This comprehensive,
multi-faceted approach to
studying genetic variation in people with DS has yielded
interesting candidate loci for follow-up
analysis.
Table of Contents
DISTRIBUTION AGREEMENT
APPROVAL SHEET
ABSTRACT COVER PAGE
ABSTRACT
COVER PAGE
ACKNOWLEDGMENTS
TABLE OF CONTENTS
LIST OF TABLES
LIST OF FIGURES
I. Introduction
I.I
Historical perspective
I.II
Epidemiology of Down syndrome
I.III
Phenotypes associated with Down syndrome
I.IV
Molecular mechanisms of heart development
I.V
Atrioventricular septal defects
I.V.i
Pathophysiology
I.V.ii
Previous studies: genetic and molecular candidates
I.VI
Models of disease in DS
I.VII Genetic variation and models of complex disease
I.VII.i
Common disease-common variant hypothesis
I.VII.ii
Common disease-rare variant hypothesis
I.VII.iii
Evidence for common and rare variant hypotheses
I.VIII Overview of research
I.IX
References
I.X
Tables
I.XI
Figures
II. Ethnicity, Sex, and the Incidence of Congenital Heart
Defects: A Report from the
National Down Syndrome
Project
II.I
Abstract
II.II
Introduction
II.III
Subjects and Methods
II.III.i
NDSP Subjects
II.III.ii
Other Subjects
II.III.iii
Clinical Information
II.III.iv
Demographic Information
II.III.v
Statistical Analysis
II.III.vi
Laboratory Studies
II.IV Results
II.IV.i
Cardiac Defects
II.IV.ii
Origin of Nondisjunction
II.IV.iii
Maternal Age
II.IV.iv
Infant Sex
II.IV.v
Maternal Ethnicity
II.IV.vi
Assessment of Ancestral Information Markers among Black Infants
II.V
Discussion
II.VI
Acknowledgements
II.VII
References
II.VIII
Tables
II.IX
Figure
III.
Variation in folate pathway genes contributes to
risk of congenital heart defects among individuals with Down
syndromes
III.I
Abstract
III.II
Introduction
III.II.i
Down Syndrome and Congenital Heart Defects (CHD)
III.III
Materials and Methods
III.III.i
Ascertainment
III.III.ii
Eligibility and Case Definitions
III.III.iii
DNA Samples
III.III.iv
Gene and SNP selection
III.III.v
Genotyping
III.III.vi
Statistical analyses
III.III.vi.a
Analysis of disomic SNPs
III.III.vi.b
Analysis of trisomic SNPs
III.III.vi.c
Covariates and Substructure
III.III.vi.d
Consideration of multiple testing
III.IV
Results
III.IV.i
Chromosome 21 Candidate Genes
III.IV.ii
Non-Chromosome 21 Candidate Genes
III.V
Discussion
III.V.i
Functional Implications
III.V.ii
Limitations and future studies
III.VI
Acknowledgements
III.VII
References
III.VIII
Tables
III.IX
Figures
IV. Genome-wide SNP association study of atrioventricular septal defects among individuals with Down syndrome
IV.I
Introduction
IV.II
Methods
IV.II.i
Ascertainment & enrollment
IV.II.ii
Array processing & sample quality control
IV.II.iii
SNP quality control
IV.II.iv
Statistical analyses
IV.II.iv.a
Non-chromosome 21
IV.II.iv.b
Chromosome 21
IV.III
Results
IV.III.i
Non-chromosome 21 analysis
IV.III.ii
Interpretation of TDT results
IV.III.iii
SNP validation
IV.III.iv
Chromosome 21 SNPs
IV.IV
Conclusions
IV.IV.i
AVSD implications
IV.V
References
IV.VI
Tables
IV.VII
Figures
V. Genome-wide CNV detection and association with atrioventricular septal defects among individuals with Down syndrome
V.I
Introduction
V.II
Methods
V.II.i
Array processing & sample quality
V.II.ii
Copy number reference samples and log2 ratio generation
V.II.iii
Generation of copy number calls
V.II.iv
Statistical analyses
V.III
Results
V.III.i
CNV counts
V.III.ii
CNV, association & candidate loci
V.IV
Conclusions
V.IV.i
Future directions
V.V
References
V.VI
Tables
V.VII
Figures
VI.
Candidate gene resequencing to identify rare
variants contributing to atrioventricular septal defects among
individuals with Down syndrome
VI.I
Introduction
VI.II
Methods
VI.II.i
Sample collection & enrollment
VI.II.ii
Sequencing
VI.II.iii
Quality control
VI.II.iv
Variant annotation & significance testing
VI.III
Results
VI.III.i
Variants identified & quality control
VI.III.ii
Association testing
VI.IV
Conclusions
VI.V
References
VI.VI
Tables
VI.VII
Figure
VII.
Conclusions
VII.I
Findings
VII.II
Future directions
VII.III
References
Appendix
A1.
Combining Microarray-based Genomic Selection (MGS)
with the Illumina Genome Analyzer Platform to Sequence Diploid
Target Regions
A1.I
Summary
A1.II
Materials and Methods
A1.III
Results
A1.IV
Discussion
A1.V
Acknowledgements
A1.VI
References
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